Reviews

Proton radiation for cancer offers the ability to conform the high-dose region of radiation therapy to the tumor while reducing the dose of radiation to adjacent normal tissues. In lung cancer, this equates to greater sparing of uninvolved lung, heart, esophagus, and spinal cord. Sparing these normal tissues permits the delivery of higher-radiation doses to the tumor. Studies that compare the distribution of radiation doses for lung cancer show that proton radiation is superior, even when factors such as respiratory motion are considered. Clinical experience confirms the feasibility of proton radiation for early-stage non-small-cell lung cancers, and clinical trials are being conducted in locally advanced tumors: To date, evidence indicates that proton radiation should be further explored.

Lung cancer remains a leading cause of cancer death in North America.[1] Non-small-cell lung cancers (NSCLCs) predominate over the small-cell variant of lung cancer, and are usually associated with a poor prognosis, owing to locally advanced or metastatic presentations. The only NSCLC subgroup that has a better than 50% five-year survival is that comprised of patients with peripherally located T1 or T2 tumors without evidence of nodal or distant metastases.[2] However, unfortunately more than 80% of patients present with stage III or IV disease.

The goal of definitive radiotherapy is to eradicate intra-thoracic disease while respecting the radiation tolerance of nearby normal structures by minimizing the dose to such structures. Various photon radiation techniques have been tried in order to effect a therapeutic advantage, among them hyperfractionation (multiple treatments per day), accelerated fractionation (shorter treatment periods), and dose escalation.[3-6] Most innovative techniques have focused on conformal treatment delivery with computer assisted three-dimensional therapy planning and, in some cases, intensity-modulated radiotherapy in which more complex treatment planning and delivery can allow the radiation oncologist to have better control of doses to healthy tissues.[7-8] Here, the goal has been to deliver higher doses to target volumes in an effort to improve local tumor control within the constraints of surrounding regions of normal tissues such as the heart, lung, esophagus, and spinal cord. Tumor control rates with photon radiation therapy, however, continue to be disappointing, in part because of the dose-limiting constraints associated with these normal structures.

FIGURE 1Percent dose deposited per depth in tissue for photon beams of various energies, and a broton beam (shown in red).

Physical Characteristics of Proton BeamsBecause of their their mass (about 1800 times that of an electron) and charge, proton beams can be controlled in three dimensions so that radiation doses can be more accurately deposited within target volumes while the dose to surrounding non-targeted tissues is often minimized—or even eliminated. This ability to spare normal tissues is an important consideration: The greater the extent to which the physician can reduce or eliminate the radiation dose to normal tissues, the lesser the likelihood that treatment will need to be compromised because of unacceptable side effects. In other words, the reduced lateral scatter and sharp dose fall-off of the proton beam not only allows delivery of the total needed dose but also affords opportunities to deliver higher doses without increasing side effects.

The importance of reducing the volume integral dose to normal tissues has been noted for years. In studies spanning more than four decades, Rubin and several collaborators identified the clinicopathologic courses of radiation injury in organs and tissues throughout the body and identified tolerance doses for those organs. Tolerances were identified in ranges of total doses in which severe or life-threatening complications were likely to occur within five years of therapeutic radiation; i.e., severe sequelae would likely occur in 5% of patients treated at the lower end of the range (TD5/5) and in 50% of patients treated to the dose at the top of the range (TD50/5).[9] Although organs and tissues were separated into categories according to their importance for survival,[10] no “safe” dose (TD0/5) was identified for any organ; rather, in a classic series of graphs, Rubin and Casarett demonstrated that sublethal doses of radiation initiate a course that can eventuate in clinical manifestations of radiation injury, some of which progress further to lethality.[11]

In later studies of relevance to lung cancer treatment, Rubin and colleagues demonstrated early and persistent elevation of cytokine production following pulmonary irradiation. The temporal relationship between elevation of specific cytokines and histological and biochemical evidence of fibrosis illustrated the continuum of response which, the authors speculated, underlies pulmonary radiation reactions and supports the concept that a perpetual cascade of cytokines is produced immediately after radiation treatment and persists until pathologic and clinical late effects are expressed.[12]

The fact that protons display a Bragg peak is what enables proton radiotherapy to offer a means of reduing the volume integral dose. In the Bragg peak, the deposited dose from a single beam is relatively low upon entrance and increases slowly until the desired depth in tissue is reached; at that point the bulk of the dose is deposited within the targeted volume, while no dose is deposited in distal tissues. The Bragg peak can be spread out to encompass the target volume while still retaining a relatively low entrance dose and sparing tissues distal to the direction of travel (Fig. 1). In non-small-cell lung cancer, and in contrast to treatment of similar target volumes with photon beams, these properties afford a great deal of sparing to the treated lung, opposite lung, heart, esophagus, and spinal cord, in turn allowing for safe dose escalation.

Because local tumor control is insufficient with conventional photon radiation treatment, and because evidence exists to indicate that higher doses may improve tumor control, investigators have anticipated a role for proton radiation therapy in patients with lung cancer. Fowler analyzed the potential use of proton radiotherapy in such cases and, using biological modeling, estimated that significant improvements in local tumor control and survival likely are possible.[13] Owing to the normal-tissue-sparing properties of proton beams, not only is there clear potential to achieve effective disease control without increased normal-tissue complications, it also may be possible to decrease the severity of toxicity seen in comparable treatments with photons. Accordingly, clinical investigations into the use of proton and other heavy-charged-particle therapies for lung cancer are being conducted at centers around the world.

FIGURE 2Planning comparison of a single lateral with photons (left) and proton beam (right).

FIGURE 3Dose-distribution for a stage I lung cancer treated with proton beam shown in axial (left) and sagittal view (right). Beams include a right lateral, right posterior oblique arrangement. Colored contours represent the percentage of the total prescribed dose.

FIGURE 4Dose distribution for a patient with stage III lung cancer treated with proton beam. Contours represent the lung tumor and involved nodes (red) and sub-clinically involved mediastinal nodes (light blue). Distribution shows the percent of the total dose. Beam arrangement includes a left lateral and posterior to the CTV (46 CGE) and a left posterior oblique to the GTV (30 CGE).

Treatment Planning: Considerations and ComparisonsAs noted, proton beams exhibit a Bragg peak effect, which yields normal-tissue sparing not possible with photon beams. This capability exists despite the special dosimetric circumstances that exist for lung cancer treatment with protons. For example, lung cancers are invariably surrounded by aerated pulmonary parenchyma; an essentially water-density-equivalent tumor is surrounded by substantially less-dense lung tissue. Aerated lung tissue has reduced stopping power compared to other soft tissues, and this affects the stopping distance or distal edge of a spread-out Bragg peak; this can cause proton beams to travel some distance beyond the distal edge of the target volume, which is not typically true of tumors located in other parts of the body. Additionally, when lung targets are selected for treatment, one must consider physiologic internal target motion, which is highly dependent on the region of the lung in which the tumor resides; i.e., tumors near the diaphragm will show the largest respiratory excursion. The simplest method to account for such motion is to measure the three-dimensional excursion of the tumor and expand the treatment volume to encompass all possible tumor positions. For small tumors (with motion parameters of less than 1 to 2 centimeters), this method is adequate—the technique has been used for patients with peripheral lung tumors of one to four centimeters in size at Loma Linda University Medical Center for more than a decade with an excellent safety profile and a low incidence of radiation pneumonitis.[14] For larger tumors and when motion parameters are greater, respiratory monitoring with beam gating, or respiratory control or compensation (perhaps via a patient-positioning device that moves the patient during treatment in a way that allows the target to remain still relative to the treatment beam) may be employed to significantly reduce dose to normal lung tissue. A report by Engelsman and colleagues compared computerized treatment plans using various techniques to account for respiratory motion in planning proton treatments.[15] Target expansion utilizing 4D treatment planning, in which the planning CT data set included multiple phases of the respiratory cycle, was found to provide the most reliable target coverage. Intrinsic pulmonary or treatment-related factors, such as pleural effusion or atelectasis, may also cause uncertainties in the stopping region of the Bragg peak, and these need to be accounted for in therapy planning. If the radiation oncologist feels that such changes may occur during the treatment course, it may be necessary to repeat chest imaging and create a new plan of treatment for any significant anatomic changes; a practice referred to as adaptive treatment planning.

Even allowing for potentially confounding factors such as these, proton-beam dosimetry is an improvement over the use of photon beams (Fig. 2). The tissue-sparing capability of the proton beam is most apparent in the treatment of early-stage non-small-cell lung cancer (Fig. 3), but significant sparing also is achievable when protons are used to treat locally advanced disease (Figs. 4 and 5).

Chang and colleagues have published a formal comparison between proton and photon treatment planning.[16] They analyzed ten patients with inoperable stage I lung cancer, comparing proton treatment plans to 3D conformal photon plans at two dose levels (66 Gy and 87.5 Gy). Analysis revealed an approximately 50% reduction in non-target lung dose when protons where used. The normal lung tissue-sparing effect seemed to be increased with the high-dose plans, indicating an additional benefit for dose escalation when proton beams are used. Fifteen patients with stage III lung cancer were also analyzed, comparing 3D photon, IMRT, and proton beam plans at two doses (63 Gy and 74 Gy). Again results showed a substantial reduction in the non-target lung dose, and again, the proton benefit seemed to be more evident with the higher dose plans. Doses to the heart, esophagus, and spinal cord were also found to be significantly reduced. This study suggests that protons can achieve higher target doses, with more significant normal-tissue sparing, than 3D conformal radiation therapy or IMRT.